tbuckley/cabot-search huggingface dataset:
PATH-48. KI-67 INDEX AS A PREDICTIVE MARKER OF MENINGIOMA CLINICO-PATHOLOGIC COURSE AND RECURRENCE FOLLOWING SURGICAL RESECTION: A RETROSPECTIVE STUDY
Authors: Mark Mizrachi, Benjamin Hartley, Shahzaib Saleem, Eric Hintz, Yonah Ziemba, Jinyu Li, Michael Schulder
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND/OBJECTIVE Meningiomas are the most common primary intracranial tumor in adults. Although usually benign, they have a variable clinical course. Ki-67, a nuclear protein involved in cell cycle regulation, has been widely studied as a marker of cellular proliferation in various cancers. However, the prognostic significance of Ki-67 in meningiomas remains controversial. Here, we investigate the Ki-67 index, as a predictive marker of meningioma recurrence following surgical resection and compare it to established prognostic markers such as WHO grade and degree of resection. METHODS The medical records of 451 consecutive patients with previously untreated cranial meningiomas who underwent resections from January 2011 to January 2021 at North Shore University Hospital (NSUH) were reviewed. Collected data included WHO grade, Ki-67 proliferative index, degree of resection, and meningioma recurrence. RESULTS There were 290 patients with grade I, 154 with grade II, and 7 with grade III meningiomas. The average post-resection follow-up period was 4 years, and 82 tumors (18%) recurred. Recurrence occurred significantly more frequently in tumors with a Ki67 index of 5 or more (31%) compared to those with a Ki67 index less than 5 (10.4%). Likewise, higher WHO grades were associated with a higher rates of recurrence, with rates of 11.3%, 27.9%, and 71.4% for grades 1, 2, and 3, respectively. Higher WHO grades also correlated with higher Ki67 scores (2.59, 10.01, and 20.71) for grades 1, 2, and 3, respectively. Additionally, a multivariate logistic regression model identified ki67, WHO grade and degree of resection as independent predictive variables for meningioma recurrence. CONCLUSION Our 10-year retrospective study suggests that the Ki67 index is a promising predictive marker for recurrence of intracranial meningioma following surgical resection. Our findings add to a growing body of data which supports inclusion of ki67 index in the WHO grading criteria.
NCMP-28. CIRCADIAN REGULATION OF NEUROINFLAMMATION DRIVING CANCER THERAPY-RELATED COGNITIVE IMPAIRMENT
Authors: Lindsey Mehl, Erin Gibson
Journal: Neuro-Oncology (2023)

Abstract More than 18 million cancer survivors were estimated to live in the United States as of January 2022. While advances in cancer detection and treatment have substantially improved survivorship, as many as 65% of patients treated for non-central nervous system tumors may develop cancer therapy-related cognitive impairment (CRCI), a neurological disorder which includes deficits in memory, attention, multitasking, fine motor function, and information processing. Our previous work found that methotrexate (MTX) chemotherapy induces persistent neuroinflammation driving CRCI in a pediatric mouse model. We now demonstrate that the time of MTX administration, called MTX chronotherapy, induces differential microglial activation and oligodendroglial dysregulation. Furthermore, we show that MTX chronotherapy alters the amount of chemotherapy that crosses the blood-brain barrier (BBB). Current experiments are elucidating the effect of various chemotherapeutics and chronotherapy on microglial activation and crosstalk with other glia. This work will reveal crucial factors regulating CRCI-associated neuroinflammation and will define novel strategies to alleviate CRCI to prioritize quality of life for cancer survivors.
CNSC-13. NEURODEVELOPMENTAL TRANSCRIPTION FACTORS PROMOTE PROLIFERATION, REGULATE CELL TYPE, AND PLAY OPPOSING ROLES IN CELLULAR MIGRATION IN GLIOBLASTOMA
Authors: Bianca Myers, Kathryn Brayer, Luis Paez-Beltran, Tou Yia Vue
Journal: Neuro-Oncology (2023)

Abstract Glioblastomas (GBM) make up ~50% of primary brain tumors and prognosis has not improved over the last 30 years. Despite high inter- and intratumoral heterogeneity, basic-helix-loop-helix (bHLH) transcription factors, ASCL1 and OLIG2, are present in the majority of tumors. Previously, we showed in patient-derived GBM xenograft (PDX-GBM) that ASCL1 binds to promoter and enhancer regions of cell cycle genes, as well as neurodevelopmental transcription factors including OLIG2. Similarly, we showed that OLIG2 binding overlaps with the majority (~90%) of ASCL1 binding sites, including at promoter and/or enhancer regions of ASCL1 and OLIG1/2 loci, illustrating their potential redundant and/or feed-forward function in GBM. It has been proposed that ASCL1 and OLIG2 contribute to the neural stem cell-like properties of tumor cells, which may promote tumor growth and progression but also the treatment resistivity and high recurrence rate of GBMs in patients. Using an immune competent glioma mouse model, we are able to efficiently induce tumors from glial progenitors surrounding the lateral ventricle while altering the levels of ASCL1 and OLIG2 to assess their combinatory roles in GBM progression. Remarkably, we found that loss of both Ascl1 and Olig2 prevents tumor formation in 80% of mice, whereas the loss of only Ascl1 resulted in reduced cellular migration from the tumor bulk while the loss of Olig2 promotes a highly migratory phenotype. Conversely, elevating the levels of Ascl1increased both tumor cell proliferation and migration similar to the loss of OLIG2. Using single cell RNA-sequencing, we found that tumor cells which express high levels of Ascl1 exhibit neural stem cell/astrocytic gene signatures, which supports ASCL1’s role as a marker of glioma-stem-cells. Collectively, these findings illustrate the role of ASCL1 and OLIG2 in regulating GBM initiation, proliferation, and migration where ASCL1 may directly be responsible for the highly invasive and proliferative phenotype of GBMs.
TMIC-73. UNRAVELING THE ALTERED EXTRACELLULAR MATRIX LANDSCAPE IN GLIOBLASTOMA AFTER RADIATION TREATMENT
Authors: Dimitra Manou, Rebecca Rosberg, Alexander Pietras
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Extracellular matrix (ECM) is a complex network of macromolecules, influencing cellular behavior and tissue integrity. Abnormal alterations in the composition and organization of the extracellular matrix have been implicated not only in the pathogenesis of numerous diseases, including cancer but are also related to the state of the disease. Despite advancements in treatment, glioblastoma (GBM) exhibits a high rate of recurrence. Tumor microenvironment (TME) plays a critical role in the regulation of cell behavior, and one important understudied tumor determinant is the ECM. Previous studies of our laboratory revealed that the matrix derived from irradiated astrocytes positively influences the stemness capacity and radio-resistance of GBM cells. MATERIAL AND METHODS The first aim of this project is to elucidate the landscape of important extracellular matrix hits in the TME of primary and recurrent GBM, using an in-house single seq database and an ECM-focused proteomic analysis in decellularized tissues. The second aim is to spatially map important neighborhoods with common crucial cell populations including astrocytes and macrophages and specialized regions such as perivascular and hypoxic niches using multiplex analysis. RESULTS AND CONCLUSIONS Preliminary data indicate a significant imbalance between fibrous components and glycans in the ECM after irradiation. In light of these considerations, our goal is to understand the TME interactions of cell populations with the matrix and the post-irradiation effect on matrix composition, aiming for an opportunity window for combinational ECM-targeted therapies.
SURG-14. THE ARRAY OF TREATMENTS AVAILABLE FOR HYPOTHALAMIC HAMARTOMA IN THE SETTING OF INTRACTABLE SEIZURE: CURRENT STATE OF THE EVIDENCE FOR ENDOSCOPIC DISCONNECTION (AND RESECTION), LITT, AND RADIOTHERAPY
Authors: Nolan Brown, Rohin Singh, Stefan Koester, Oanh Nguyen, Basel Musmar, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract Numerous minimally invasive approaches to hypothalamic hamartomas (HHs) have been developed though their efficacy in treating seizures has not been closely analyzed. A systematic review was performed using three databases per PRISMA in order to identify all studies comparing seizure outcomes for HHs treated via endoscopic disconnection (ED), resection (ER), ablation, and radiosurgery. Of the initial 235 studies, 67 studies which reported individual patient data were included for analysis encompassing a total of 229 patients (75/219 females). ED: A total of 82 (33 females, 40%) patients were treated via endoscopic disconnection. Mean follow-up was 18 months and 39 patients (48%) were Engel Class (EC) I, 23 patients (28%) were EC II, 15 patients (18%) were EC III, and 4 patients (4.9%) were EC IV. ER: A total of 31 (8 females, 26%) patients were treated via endoscopic resection. Mean follow-up was 18 months and 14 patients (45%) were Engel Class (EC) I, 8 patients (26%) were EC II, 0 patients (0%) were EC III, and 9 patients (29%) were EC IV. Ablation: A total of 83 (24 females, 32%) patients were treated via either LiTT or thermal ablation. Mean follow-up was 16 months and 57 patients (69%) were Engel Class (EC) I, 12 patients (14%) were EC II, 4 patients (4.8%) were EC III, and 10 patients (12%) were EC IV. Radiotherapy: A total of 33 (10, 32%) patients were treated via radiotherapy. Mean follow-up was 32 months and 18 patients (55%) were Engel Class (EC) I, 9 patients (27%) were EC II, 3 patients (9.1%) were EC III, and 3 patients (9.1%) were EC IV. Our findings suggest that patients treated with ablation had the highest percentage of seizure freedom, followed by radiotherapy, endoscopic disconnection, and endoscopic resection. Further studies are needed to determine the long-term efficacy and safety.
TMIC-44. THY1 CONFERS PROLIFERATIVE ADVANTAGES AND THERAPY RESISTANCE WITHIN LOCALIZED NICHES OF GLIOMA
Authors: Visweswaran Ravikumar, Sunita Shankar, Sunjong Ji, Zainab Hassan, Yacoub Haydin, Dah-Luen Huang, Ziad Fehmi, Alnawaz Rehemtulla, Arvind Rao, Wajd Al-holou
Journal: Neuro-Oncology (2023)

Abstract Resistance to therapy is a hallmark of Glioblastoma (GBM), making it a deadly disease. Earlier, using a longitudinal mouse model, we reported that the immunoglobulin-like cell surface receptor THY1, was significantly upregulated in recurrent GBM tumors. Here, we used single cell and spatial transcriptomics data to track THY1 expression through treatment resistance. Single cell analysis of primary and recurrent GBM shows that THY1 expression is significantly associated with multiple tumor cell states, namely, the NPC-like (Neuronal precursor-like), OPC-like (oligodendrocyte precursor-like) and MES-like (mesenchymal-like) cellular states. Further, spatial analysis of primary GBM shows that tumor cells resident in highly vascularized regions and at invasive edges express significantly high levels of THY1. Specifically, high THY1 levels at the invasive edge is associated with NPC-like state, known to migrate through white matter tracts in vascular regions. In contrast, THY1 expression is high in MES-like cells within recurrent GBM tumor cells. Single cell analysis of a matched primary and recurrent tissue shows a remarkable increase in THY1 expression upon recurrence coincident with a switch to predominantly MES-like state. Using protein markers that define different cellular states we performed immunofluorescence analyses to track the expression of THY1 across both primary and recurrent tumors. We show evidence of high THY1 protein expression associated with NPC-like cells in different niches within primary tumors. In recurrent GBM tissues, THY1 protein expression is significantly higher and present along the palisading regions surrounding necrosis. Finally, we show that dox inducible knockout of THY1 completely abrogates the ability of a patient derived organoid to establish tumors in mice. We are currently exploring this model to study the role of THY1 in therapy resistance. Together, these data suggest that THY1 is critical for tumor growth and upon therapeutic stress can contribute towards shift in tumor cell identity to generate therapy-resistant clonal populations.
NCMP-29. THE NATURAL HISTORY OF NEUROLYMPHOMATOSIS
Authors: Elizabeth Xu, Quan Ho, Ashley Liu, Shiva Gautam, Eric Wong
Journal: Neuro-Oncology (2023)

Abstract Neurolymphomatosis is a rare lymphoid malignancy of the peripheral nervous system. Patients suffer from debilitating neurological deficits due to lymphoma invasion into one or more peripheral nerves and the natural history of this disease is still poorly understood. We performed a PubMed search and extracted data on year of publication, age, gender, type of lymphoma, nerves involved, imaging modalities, treatment received, and survival times. Kaplan-Meier statistics were used to determine outcome parameters over time and compare prognostic factors. Multiple comparisons were done to determine differences among groups. Our search identified 559 patients from 286 articles. Median age was 61 years (range 2-92) from 326 males, 222 females, and 11 with unspecified gender. Median overall survival (OS) was 12.0 months (range 10.0-15.0) for the entire cohort. Most frequent histologies were diffuse large B-cell lymphoma, unspecified T-cell lymphoma, and unspecified B-cell lymphoma, involving the brachial plexus, cranial nerves, and sciatic nerve. None had molecular profiling. There was a progressive lengthening of OS in successive decades, from 0.5 (95%CI 0.0-0.8) to 26.4 (95%CI 18.0-34.8) months from 1951-2022 (r2=0.9432, p&amp;lt; 0.001). Time from first treatment to progression also increased from 2.0 (95%CI N/A) to 28.3 (95%CI 23.1-33.5) months (r2=0.6923, p&amp;lt; 0.001). However, time from symptom onset to diagnosis remained unchanged during this period (r2=0.6206, p=0.277). Patients were most frequently treated with methotrexate-based chemotherapies (n=81), rituximab-based chemotherapies (n=176), and/or radiation (n=79). Only 12 received 3 or more regimens. Primary neurolymphomatosis had a better prognosis than secondary neurolymphomatosis, median OS 15.0 (95%CI 11.0-33.0) vs. 10.0 (95%CI 10.0-10.0) months (p=0.016). No OS difference was noted between B- and T-cell disease (p=0.4393), while patients with low-grade B-cell neurolymphomatosis did better than those with Burkitt's lymphoma (p≤0.001). Outcome for patients with neurolymphomatosis has improved over time. But timely diagnosis remains a major problem that needs improvement.
CTIM-37. A PILOT STUDY OF AXICABTAGENE CILOLEUCEL (AXI-CEL) FOR THE TREATMENT OF RELAPSED/REFRACTORY PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL AND SCNSL)
Authors: Lakshmi Nayak, Caroline Falvey, Riemke Bouvier, Ugonma Chukwueke, Sarah Hogan, Elizabeth Kendricken, Christopher Meehan, Robert Redd, Jennifer Fisher, Alexandra Torres, Julia Jones, Eudocia Lee, Austin Kim, Luis Nicolas Gonzalez Castro, Jose Ricardo McFaline-Figueroa, Elisa Aquilanti, Gilbert Youssef, Isabel Arrillaga-Romany, Mark Murakami, Lynette Sholl, David Meredith, Raymond Y Huang, Linda Ramsdell, Ulrike Gerdemann, Paula Keskula, Jim Kaminski, Alexandre Albanese, Wenya Linda Bi, Omar Arnaout, David Reardon, Patrick Wen, Soumya Poddar, Daqin Mao, Mike Mattie, Madison Davis, Simone Filosto, Leslie Kean, Philippe Armand, Caron Jacobson
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Optimal therapy for patients with relapsed/refractory (R/R) CNSL is not defined, and their prognosis is poor. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel(axi-cel) has demonstrated superior efficacy over standard of care in R/R systemic diffuse large B-cell lymphoma and could be an effective regimen for R/R CNSL. METHODS This is a pilot study of axi-cel in patients with R/R CNSL. Only corticosteroids were allowed for bridging. Patients underwent lymphodepletion with fludarabine and cyclophosphamide followed by standard axi-cel dosing of 2x106 cells/kg infusion. An Ommaya reservoir was placed prior to infusion. The first 6 patients enrolled were observed for treatment-limiting toxicities(TLTs). The study enrolled a total of 17 patients. Primary endpoint was safety, measured by rate of TLTs and grade 3+ adverse events(AEs). Secondary endpoints included objective response rate(ORR), complete response(CR) rate, duration of response(DOR), progression-free survival(PFS) and overall survival(OS). Exploratory analyses included paired peripheral blood and CSF analyses for axi-cel pharmacokinetics, cytokine levels, flow cytometry, single-cell RNA-Seq and circulating tumor-DNA. RESULTS We report the results of all 17 patients(13 PCNSL, 4 SCNSL) enrolled. Median age was 64 years (34-80), 8/17 were women. As of 6/2023, 14 treated patients had &amp;gt;1 month follow-up, with 86%(12/14) ORR and 64%(9/14) CR. Six patients progressed. No TLTs were observed; 15/16(94%) patients developed cytokine release syndrome/CRS (grade 3+, 0%), 8/16(50%) developed immune effector cell-associated neurologic syndrome/ICANS, (grade 3+, 5/16(31%)). PFS, OS, DOR and correlatives will be reported at the meeting. Daily examination of CAR T-cells in blood and CSF by scRNA-Seq revealed evolution of a prominent Type I interferon (IFN) transcriptomic signature of CAR-Ts in the CSF. CONCLUSION Axi-cel is safe and well-tolerated in CNSL patients with promising efficacy and no apparent additional risk of adverse neurologic events including ICANS. IFN pathway may play a major role in CAR-T efficacy in CNSL.
BIOM-50. EXOSOMAL MICRORNA EXPRESSION SIGNATURE IN BLOOD AND CEREBROSPINAL FLUID OF GLIOBLASTOMA PATIENTS
Authors: Daisuke Yamashita, Satoshi Suehiro, Masahiro Nishikawa, Akihiro Inoue, Takeharu Kunieda
Journal: Neuro-Oncology (2023)

Abstract Analysis of exosomes derived from plasma or cerebrospinal fluid (CSF) has emerged as a promising biomarker platform for therapeutic monitoring in glioblastoma patients. However, the contents of the various subpopulations of exosomes in these clinical specimens remain poorly defined. Here we characterize the relative abundance of miRNA species in exosomes derived from the plasma and CSF of glioblastoma patients. To this end, we first employed miRNA arrays to measure the expression of exosomal miRNAs in the plasma from glioblastoma patients (n = 24) and healthy volunteers (n = 7) as control. In addition, we performed global miRNA profiling of exosomal miRNAs in the CSF from glioblastoma patients (n = 5) and non-tumoral patients (n = 3; hydrocephalus patients) as control. In plasma derived exosomes, 80 miRNAs were altered by &amp;gt;2-fold in glioblastoma patients compared to controls. In CSF, 92 miRNAs were altered by &amp;gt;2-fold in glioblastoma patients compared to controls. Combined analysis of plasma and CSF revealed a similar fold difference in eight miRNAs. Next, we measured these eight miRNAs expression in in the plasma from pre- and post-operative glioblastoma patients (n = 9). Among these eight miRNAs, we identified only one miRNA (miR-34b-3p) that was upregulated in exosomes from pre-operative glioblastoma patients. Our results suggest that miR-34b-3p might have a potential as a novel diagnostic marker or a therapeutic tool for glioblastoma patients.
NCMP-24. RECURRENT BOUTS OF SCURVY DURING GLIOBLASTOMA REMISSION
Authors: Alipi Bonm, Hicks Katherine, Jerome Graber
Journal: Neuro-Oncology (2023)

Abstract Various nutritional deficiencies are more common in patients with cancer, including thiamine, iron and vitamin B12 deficiences, and can be associated with metabolic stress, treatments given and reduced nutritional intake or absorption. Vitamin C deficiency and scurvy have also been reported as a rare complication in cancer patients, but are not frequently seen in the developed countries. We report a 29 year old woman who underwent partial resection of a bifrontal isocitrate dehydrogenase, methylated glioblastoma followed by radiation and temozolomide four years prior. Her tumor remained stable since that time, but she had ongoing decreased appetite and sensitivity to food smells and tastes, which restricted her diet substantially. She had mild chronic anemia and was underweight, but had remained stable. She presented to us with acutely worsening fatigue, lower limb edema and a new rash that was superficially petechial in appearance. She had gingival hyperplasia and friability, and a jaundiced appearance. No deep venous thrombosis was found and liver tests were normal, giving a picture of scurvy. Her serum vitamin C level was undetectable, B12 was 75, folate 3.4, hemoglobin 6.1, albumin 3.2 and vitamin D 11.5. She was given intravenous and oral ascorbic acid as well as other supplementation and had immediate resolution of limb swelling and greatly improved appetite and energy. One year later, with glioblastoma still stable off treatment, she had recurrent worsening fatigue, appetite and gingivitis, and typical petechia-like rash appeared within minutes of IV placement for MRI contrast in the associated vein. She declined repeat serum testing but symptoms resolved on resuming high dose oral vitamin supplementation. Vitamin C has been studied as a supplement in glioblastomas, but also shown to reduce etoposide toxicity. Vitamin C and other nutritional deficiencies may be more common in brain tumor patients, but under-diagnosed.
SURG-19. RE-PURPOSING DEEP BRAIN STIMULATORS AS ELECTRIC FIELD THERAPY (EFT) AS TREATMENT FOR GLIOBLASTOMA
Authors: Jun Ma, Sanjay Dhawan, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Though alternating electric field therapy (EFT) for glioblastoma received FDA approval, biophysical modeling suggests that field strength generated by scalp electrodes may not sufficiently extend to deep, subcortical regions. Objective: We explore the anti-tumor activity of electric field (EF) generated by electrode directly implanted into glioblastomas, with the goal of repurposing deep brain stimulators as a therapeutic platform. Method: Laboratory characterization and murine modeling Result: In vitro, activation of leads of a deep brain stimulator induced tumoricidal activity within the region encompassed by the EF. To further characterized this tumoricidal activity, a customized two-electrode array was designed and fabricated to allow study of glioblastoma cells seeded at the center of the EF. Consistent with the observations made using the deep brain stimulator electrode, electric field therapy (EFT) induced both necrosis and apoptosis of glioblastoma cells. To characterize this effect in vivo, a four-electrode array was designed and fabricated such that tumor cells can be implanted through a center channel equidistant the electrodes. Mice were implanted with this array, followed by luciferase labelled murine glioblastomas through the center channel. After tumor engravement, mice were randomized to EFT or placebo. EFT was associated with significant diminishment of tumor growth (measured by bio- bioluminescence) and prolonged survival. Analysis of brain sections following EFT showed a notable increase in peri-tumoral microglia accumulation, suggesting potential of EFT as an immune-modulation platform. CONCLUSION Our results suggest therapeutic potential for repurposing of deep brain stimulator as glioblastoma therapy, with opportunities for therapeutic enhancement through novel electrode design and stimulation parameter modulation.